brain sciences Review Whole-Brain Models to Explore Altered States of Consciousness from the Bottom Up Rodrigo Cofré 1,* , Rubén Herzog 2 , Pedro A.M. Mediano 3 , Juan Piccinini 4,5, Fernando E. Rosas 6,7,8 , Yonatan Sanz Perl 4,9 and Enzo Tagliazucchi 4,5 1 CIMFAV-Ingemat, Facultad de Ingeniería, Universidad de Valparaíso, Valparaíso 2340000, Chile 2 Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso 2360103, Chile; [email protected] 3 Department of Psychology, University of Cambridge, Cambridge CB2 3EB, UK; [email protected] 4 National Scientific and Technical Research Council, Buenos Aires C1033AAJ, Argentina; [email protected] (J.P.); [email protected] (Y.S.P.); [email protected] (E.T.) 5 Buenos Aires Physics Institute and Physics Department, University of Buenos Aires, Buenos Aires C1428EGA, Argentina 6 Centre for Psychedelic Research, Department of Brain Science, Imperial College London, London SW7 2DD, UK; [email protected] 7 Data Science Institute, Imperial College London, London SW7 2AZ, UK 8 Centre for Complexity Science, Imperial College London, London SW7 2AZ, UK 9 Departamento de Matemáticas y Ciencias, Universidad de San Andrés, Buenos Aires B1644BID, Argentina * Correspondence: [email protected] Received: 26 July 2020; Accepted: 7 September 2020; Published: 10 September 2020 Abstract: The scope of human consciousness includes states departing from what most of us experience as ordinary wakefulness. These altered states of consciousness constitute a prime opportunity to study how global changes in brain activity relate to different varieties of subjective experience. We consider the problem of explaining how global signatures of altered consciousness arise from the interplay between large-scale connectivity and local dynamical rules that can be traced to known properties of neural tissue. For this purpose, we advocate a research program aimed at bridging the gap between bottom-up generative models of whole-brain activity and the top-down signatures proposed by theories of consciousness. Throughout this paper, we define altered states of consciousness, discuss relevant signatures of consciousness observed in brain activity, and introduce whole-brain models to explore the biophysics of altered consciousness from the bottom-up. We discuss the potential of our proposal in view of the current state of the art, give specific examples of how this research agenda might play out, and emphasize how a systematic investigation of altered states of consciousness via bottom-up modeling may help us better understand the biophysical, informational, and dynamical underpinnings of consciousness. Keywords: whole-brain models; altered states of consciousness; signatures of consciousness; integrated information theory; psychedelics 1. Introduction Consciousness has been a puzzle beyond the scope of natural science for centuries; however, the significant progress seen during the last 30 years of research suggests that a rigorous scientific understanding of consciousness is possible [1–3]. The dawn of the modern neuroscientific approach to consciousness can be traced back to Crick and Koch’s proposal for identifying the neural correlates of consciousness (NCC) [4,5], understood as the minimal set of neural events associated with a certain subjective experience. The key intuition that fuels this proposal is that careful experimentation Brain Sci. 2020, 10, 626; doi:10.3390/brainsci10090626 www.mdpi.com/journal/brainsci Brain Sci. 2020, 10, 626 2 of 29 should suffice to reveal brain events that are systematically associated with conscious (as opposed to unconscious or subliminal) perception. Needless to say, the methodological challenges associated with this idea are vast—particularly concerning the determination of what constitutes conscious content (e.g., must content be explicitly reported, or are other less direct forms of inference equally valid [6,7])? Despite these problems, which are still actively debated, the program put forward by Crick and Koch succeeded to jump-start contemporary consciousness research. For recent reviews on the empirical search for NCC, see Ref. [8]; for a theoretical examination of the concept of NCC, see Ref. [9]; and for criticism to the concept of NCC, see Refs. [10,11]. While the quest for the NCC aims to provide answers to where and when consciousness occurs in the brain, subsequent theoretical efforts have attempted to discover systematic signatures within those NCC that could reflect key mechanisms underlying the emergence of consciousness. In other words, these efforts try to answer how consciousness emerges from the processes that give rise to the NCC [12,13]. Hence, theoretical models of consciousness strive to “compress” our empirical knowledge of the NCC, i.e., to provide rules that can predict when and where from how. The nature of those rules, in turn, determines the kind of explanation offered by a theoretical model of consciousness. Here, we consider two possible approaches: top-down and bottom-up [14]. On the one hand, top-down approaches start by identifying high-level signatures of consciousness, and then try to narrow down low-level biophysical mechanisms compatible with those signatures. On the other hand, bottom-up approaches build from dynamical rules of elementary units (such as neurons or groups of neurons [15]) and attempt to provide quantitative predictions by exploring the aggregated consequences of these rules across various temporal and spatial scales. We further subdivide explanations into those addressing conscious information access (e.g., perception in different sensory modalities) and those concerning consciousness as a temporally extended state, such as wakefulness, sleep, anaesthesia, and the altered states that can be elicited by pharmacological manipulation [16–22]. Our objective is to put forward a research program for the development of bottom-up explanations for the relationship between brain activity and states of consciousness, which we claim is underrepresented both in past and current research. Theories that rely heavily on a top-down perspective risk being under-determined in the reductive sense, i.e., they could be compatible with multiple and potentially divergent lower-level biological and physical mechanisms [23]. While we do not know whether consciousness may be instantiated in other physical systems, we certainly do know that it is instantiated in the human brain, and therefore all theoretical models of consciousness should be consistent with the low-level biophysical details of the brain to be considered acceptable. In light of this potential under-determination, it is difficult to decide whether the different theories currently dominating the field are competing (in the sense of predicting mutually contradictory empirical findings) or convergent (in spite of being formulated from disparate perspectives). Without investigating theories of consciousness from the bottom-up, it could be simply too early for proposals of an experimentum crucis to decide between candidates [24]. In this paper, we posit that computational models can play a crucial role in determining the low-level physical and biological mechanisms fulfilling the high-level phenomenological and computational constraints of theoretical models of consciousness. The idea that consciousness is intrinsically dependent on the dynamics of neural activity is not new, and, in this sense, we follow the trail of pioneers, such as Walter J. Freeman [25], Francisco Varela [26], and Gerald Edelman [27], among others. However, our proposal reaches further than these previous attempts by building upon the technological and conceptual advances accumulated over the last decades. In particular, the widespread availability of non-invasive neuroimaging methods (functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), magnetoencephalography (MEG)) has expanded our knowledge of the functional and structural aspects of the brain, while the development of connectomics has revealed the intricate meso- and macroscopic connectivity patterns that wire cortical and subcortical structures together [28]. Moreover, for the first time, there is sufficient empirical data and computational power available to construct whole-brain models with real predictive Brain Sci. 2020, 10, 626 3 of 29 power [15,29,30], which represents a radical improvement over past research efforts. We expect that these advances will enable us to compare the predictions of theories of consciousness by means of whole-brain computational models that can be directly contrasted with empirical results. In the following, we adopt and explore the consequences of this perspective. Our proposal and its justification are structured as follows. First, Section2 describes several examples of altered states of consciousness and briefly discusses some proposed general definitions. Next, Section3 introduces top-down approaches for quantifying and classifying states of consciousness solely from functional data. Then, Section4 introduces the main technical ideas underlying the development of whole-brain computational models, highlighting novel results with special emphasis on those informing research on altered states of consciousness. Section5 discusses how computational models can contribute to overcome open challenges and conceptual difficulties, thus providing new insights into the study of altered states of consciousness. Finally, Section6 elaborates on possible future directions of research